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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization

International Bureau

(43) International Publication Date
9 March 2006 (09.03.2006)

PCT

(10) International Publication Number

WO 2006/026501 Al

(51) International Patent Classification:
A61K9/14 (2006.01)

(21) International Application Number:

PCTYUS2005/030542

(22) International Filing Date: 29 August 2005 (29.08.2005)

(25) Filing Language:

(26) Publication Language:

English

(30) Priority Data:

60/604,753

27 August 2004 (27.08.2004) US

(71) Applicant (for all designated States except US): BAYER
PHARMACEUTICALS CORPORATION [US/US];
400 Morgan Lane, West Haven, CT 06516-4175 (US).

(72) Inventor; and

(75) Inventor/Applicant (for US only): SCHUECKLER,
Fritz; An den Weihern 42, 5 1467 Bergisch Gladbach (DE).

(74) Agents: TRAVERSO, Richard et al.; Millen, White, Ze
lano & Branigan, P.C., Suite 1400, Arlington Courthouse
Plaza 1, 2200 Clarendon Boulevard, Arlington, VA 22201
(US).

(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
KG, KM, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA,
MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ,
OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL,
SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC,
VN, YU, ZA, ZM, ZW

(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
GN, GQ, GW, ML, MR, NE, SN, TD, TG).

Published:

— with international search report

— before the expiration of the time limit for amending the
claims and to be republished in the event of receipt of
amendments

For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.

(54) Title: NEW PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF CANCER

(I)

(57) Abstract: This invention relates to novel pharmaceutical compositions comprising a solid dispersion of the compound of
Formula (I), to processes for preparing these novel pharmaceutical compositions and to their use for treating hyper-proliferative
disorders, such as cancer, either as a sole agent or in combination with other therapies.

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New Pharmaceutical Compositions for the Treatment of Cancer

This application claims the benefit of the filing date of U.S. Provisional
Application Serial No. 60/604 J 5 3 filed August 27, 2004, which is incorporated by
reference herein.

Field of the Invention

This invention relates to novel pharmaceutical compositions, to processes for
preparing these novel pharmaceutical compositions and to their use for treating hyper-
proliferative disorders, such as cancer, either as a sole agent or in combination with
other therapies.

Background of the Invention

Diarylureas are a class of serine-threonine kinase inhibitors as well as tyrosine kinase
inhibitors known in the art. The following publications illustrate their utility as active
ingredient in pharmaceutical compositions for the treatment of hyper-proliferative
diseases, such as cancer:

Smith et aL, Bioorg. Med. Chem. Lett. 2001, 77, 2775-2778.
Lowinger et al. s Clin. Cancer Res. 2000, 6(suppl), 335.
Lyons et aL, Endocr.-Relat. Cancer 2001, 8 9 219-225.

Riedl et aL, Book of Abstracts, 92 nd AACR Meeting, New Orleans, LA, USA, abstract
4956.

Khire et aL, Book of Abstracts, 93 rd AACR Meeting, San Francisco, CA, USA, abstract
4211.

Lowinger et aL, Curr. Pharm. Design 2002, 5, 99-1 10.

Carter et aL, Book of Abstracts, 92 nd AACR Meeting, New Orleans, LA, USA, abstract
4954.

Vincent et aL, Book of Abstracts, 38 th ASCO Meeting, Orlando, FL, USA, abstract
1900.

Hilger et aL, Book of Abstracts, 38 th ASCO Meeting, Orlando, FL, USA, abstract
1916.

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Moore et al., Book of Abstracts, 38 ASCO Meeting, Orlando, FL, USA, abstract
1816.

Strumberg et al., Book of Abstracts, 38 th ASCO Meeting, Orlando, FL, USA, abstract
121.

Omega-Carboxyaryl diphenyl ureas are disclosed in WO00/42012 (published July 20,
2000), WO00/41698 (published July 20, 2000), and in the following published U.S.
applications:

US2002-0165394-A1, published November 7, 2002,
US2001-003447-A1, published October 25, 2001,
US2001-0016659-A1, published August 23, 2001,
US2002-013774-A1, published September 26, 2002,

and copending U.S. applications:
09/758,547, filed January 12, 2001,
09/889,227, filed July 12, 2001,
09/993,647, filed November 27, 2001,
10/042,203, filed January 1 1, 2002 and
10/071,248, filed February 11, 2002

In particular, it has been discovered that the diphenyl urea of Formula I, also referred
as "BAY 43-9006" or 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-
pyridine-2-carboxylic acid methyl amide, is a potent inhibitor of raf, VEGFR-2, p38,
and PDGFR kinases. These enzymes are all molecular targets of interest for the
treatment of hyper-proliferative diseases, including cancer. Therefore, the compound
of Formula I will be used as medicine for the treatment of the above mentioned
diseases.

A preferred route of drug administration is through the oral cavity. This route
provides great comfort and convenience of dosing. The bioavailability achieved after
oral administration is a measure for the potential usefulness of an oral dosage form of
a drug. Bioavailability after oral application depends on several factors, such as

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solubility of the active in aqueous media, dose strength, dissolution of the dosage
form, absorption throughout the gastrointestinal tract and first pass effect.
Therefore solid pharmaceutical compositions for oral application containing the
compound of Formula I, which result in improved dissolution, absorption and
exposure in mammals, improved inter-patient variability, and overall improved
efficacy in the clinic are desired.

Description of the Invention

Pharmaceutical compositions comprising a solid dispersion of the compound of
Formula I below are provided.

Formula I is as follows:

The term "the compound of Formula I", or "the compound of this invention" does not
only refer to 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-
carboxylic acid methyl amide as depicted in Formula I, but also refers to its solvates,
hydrates, pharmaceutically acceptable salts, or a combination thereof.

The present invention pertains to

(i) novel pharmaceutical compositions containing the compound of Formula I in
the form of a solid dispersion, which includes solid solutions, glass solutions,
glass suspensions, amorphous precipitations in a crystalline carrier, eutectics
or monotecics, compound or complex formation and combinations thereof,

(ii) processes for preparing these novel pharmaceutical compositions, and

(iii) the use of these compositions for the treatment of hyper-proliferative diseases,
such as cancer, either as a sole agent, or in combination with other anti-cancer
therapies.

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In the following, the different types of solid dispersions (solid solutions, glass
solutions, glass suspensions, amorphous precipitations in a crystalline carrier,
eutectics or monotecics, compound or complex formation and combinations thereof)
are collectively referred to as "solid dispersion."

A pharmaceutical composition according to this invention comprises of a solid
dispersion comprising at least the compound of Formula I and a pharmaceutical ly
acceptable matrix.

The term "matrix" or "matrix agents" as used herein refers to both polymeric
excipients, non-polymeric excipients and combinations thereof, capable of dissolving
or dispersing the compound of formula L

An aspect of the invention of particular interest is a pharmaceutical composition
comprising a solid dispersion, wherein the matrix comprises a pharmaceutically
acceptable polymer, such as polyvinylpyrrolidone, vinylpyrrolidone/vinylacetate
copolymer, polyalkylene glycol (i.e. polyethylene glycol), hydroxyalkyl cellulose (i.e.
hydroxypropyl cellulose), hydroxyalkyl methyl cellulose (i.e. hydroxypropyl methyl
cellulose), carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose,
polymethacrylates, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate
copolymer, polyglycolized glycerides, xanthan gum, carrageenan, chitosan, chitin,
poyldextrin, dextrin, starch, proteins or combinations thereof

Another aspect of the invention is a pharmaceutical composition comprising a solid
dispersion, wherein the matrix comprises a sugar and/or sugar alcohol and/or
cyclodextrin, for example sucrose, lactose, fructose, maltose, raffinose, sorbitol,
lactitol, mannitol, maltitol, erythritol, inositol, trehalose, isomalt, inulin, maltodextrin,
p-cyclodextrin, hydroxypropyl-p-cyclodextrin, sulfobutyl ether cyclodextrin or
combinations thereof.

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An aspect of the invention of particular interest is a pharmaceutical composition
comprising a solid dispersion which is an amorphous co-precipitate of a compound of
Formula I and polyvinylpyrrolidone.

Additional suitable excipients that are useful in the formation of the matrix of the
solid dispersion include, but are not limited to alcohols, organic acids, organic bases,
amino acids, phospholipids, waxes, salts, fatty acid esters, polyoxy ethylene sorbitan
fatty acid esters, and urea.

The solid dispersion of the compound of Formula I in the matrix may contain certain
additional pharmaceutical acceptable ingredients, such as carriers, surfactants, fillers,
disintegrants, recrystallization inhibitors, plasticizers, defoamers, antioxidants,
detackifier, pH-modifiers, glidants and lubricants.

A carrier according to this invention is an excipient, which becomes loaded with a
mixture, comprised of at least the matrix agent and the compound of this invention,
during the manufacturing process of the solid dispersion, for example by hot melt
extrusion, hot melt coating, prilling, congealing, solvent evaporation processes (e.g.
layering, coating, granulation), and thus becomes an integral part of the solid
dispersion.

In an embodiment of this invention, the matrix comprises a water soluble polymer.

In another embodiment, at least one from the group of polyvinylpyrrolidone,
copovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene
glycol and polyethylene oxide is used as matrix agent in the solid dispersion.

In another embodiment, polyvinylpyrrolidone is used as matrix agent.

Another embodiment comprises hydroxypropyl cellulose as matrix agent.

Another aspect of the invention of particular interest are solid dispersions containing
croscarmellose sodium, sodium starch glycollate, crospovidone, low substituted

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hydroxypropyl cellulose (L-HPC), starch, microcrystalline cellulose or a combination
thereof as carrier or disintegrant.

In an embodiment, the solid dispersion comprises polyvinylpyrrolidone and
croscarmellose sodium.

In another embodiment, the solid dispersion comprises polyvinylpyrrolidone and
sodium starch glycollate.

In another embodiment, the solid dispersion comprises polyvinylpyrrolidone,
croscarmellose sodium and microcrystalline cellulose.

In another embodiment, the solid dispersion comprises hydroxypropyl cellulose and
croscarmellose sodium.

In yet another embodiment, the solid dispersion comprises hydroxypropyl cellulose
and at least one excipient, which is a sugar, sugar alcohol, cyclodextrin or
combination thereof.

The solid dispersion of the invention is prepared according to methods known to the
art for the manufacture of solid dispersions, such as fusion/melt technology, hot melt
coating, prilling, congealing, solvent evaporation (e.g. freeze drying, spray drying,
vacuum drying, layering of powders of granules, powders or pellets an fluid bed
granulation), coprecipitation, supercritical fluid technology and electrostatic spinning
method.

Hot melt extrusion or solvent evaporation techniques are suitable processes for
preparation of solid dispersion formulations of this invention.

A solvent suitable for manufacture of solid dispersions by solvent evaporation
processes such as spray-drying, layering and fluid-bed granulation can be any

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compound, wherein the compound of Formula I can be dissolved. Preferred solvents
include alcohols (e.g. methanol, ethanol, n-propanol, isopropanol, and butanol),
ketones (e.g. acetone, methyl ethyl ketone and methyl isobutyl ketone), esters (e.g.
ethyl acetate and propyl acetate) and various other solvents such as acetonitrile,
methylene chloride, choroform, hexane, toluene, tetrahydrofuran, cyclic ethers, and
1,1,1-trichloroethane. Lower volatility solvents, such as dimethyl acetamide or
dimethylsulfoxide can also be used. Mixtures of solvents, can also be used, as can
mixtures with water as long as the drug and if necessary the matrix agent are
sufficiently soluble to make the process practicable.

An aspect of the invention of particular interest is a pharmaceutical composition in
which the compound of Formula I is substantially amorphous.

Another aspect of the invention of particular interest is a solid dispersion of the
compound of Formula I, wherein the matrix is a polyvinylpyrrolidone polymer.

Another aspect of the invention of particular interest is a solid dispersion of the
compound of Formula I, wherein the matrix is a hydroxypropylcellulose polymer.

Another aspect of this invention which is of particular interest is a novel
pharmaceutical composition comprising a co-precipitate of a compound of formula I
and a matrix.

This pharmaceutical composition will be utilized to achieve the desired
pharmacological effect by oral administration to a patient in need thereof, and will be
advantageous to a conventional formulation in terms of drug release, bioavailability,
and/or interpatient variability in mammals. A patient, for the purpose of this
invention, is a mammal, including a human, in need of treatment for the particular
condition or disease, including prophylactic treatment.

For oral administration, the solid dispersion described herein can be formulated into
solid or liquid preparations such as powder, granules, pellets, tablets, capsules,
drag^es, chewable tablets, dispersible tables, troches, lozenges, melts, solutions,

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suspensions, or emulsions, and may be prepared according to methods known to the
art for the manufacture of pharmaceutical compositions. For this purpose the solid
dispersion may be compounded with conventional excipients, for example binders,
fillers, lubricants, disintegrants, solvents, surfactants, thickeners and stabilizers,
coating materials as well as flavoring agents, sweeteners, flavoring and coloring
agents.

It is believed that one skilled in the art, utilizing the preceding information, can utilize
the present invention to its fullest extent. The oral formulation of the compound of
Formula I refers to a wide range of dosages such as 1 mg, 10 mg, 100 mg, or even 1 g
daily dosing and beyond. This would be accomplished, for example, by modifying the
composition and size of the tablet or capsule, and/or by administering multiple tablets
or capsules per day to the patient in need thereof. Alternatively, the solid dispersion
formulation may also be dosed in forms such as powders, granules, chewable or
dispersible tablets, or by dispersions of any adequate solid formulation in a suitable
liquid prior to use, for example if the optimal dose regimen was no longer consistent
with a feasible tablet or capsule size.

Method of treating hyper-proliferative disorders

The present invention also relates to a method for using a new oral pharmaceutical
composition of the compound of Formula I to treat mammalian hyper-proliferative
disorders, including cancer. This method comprises administering the pharmaceutical
composition in the form of a solid dispersion to a mammal in need thereof, including
a human, an amount which is effective to treat the disorder. The term "hyper-
proliferative disorders" and/or "cancer" not only refers to solid tumors, such as
cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract,
urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant
metastases, but also includes lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma,
invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

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Examples of cancers of the respiratory tract include, but are not limited to small-cell
and non-small-cell lung carcinoma, as well as bronchial adenoma and
pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem and hypophtalmic
glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well
as neuroectodermal and pineal tumor.

Tumors of the male reproductive organs include, but are not limited to prostate and
testicular cancer. Tumors of the female reproductive organs include, but are not
limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as
sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal, colon, colorectal,
esophageal, gallbladder, gastric, pancreatic, rectal, small intestine, and salivary gland
cancers.

Tumors of the urinary tract include, but are not limited to bladder, penile, kidney,
renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellular carcinoma
(liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma
(intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's
sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin
cancer.

Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal /
nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's
lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the
central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue, fibrosarcoma,
osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and
rhabdomyosarcoma.

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Leukemias include, but are not limited to acute myeloid leukemia, acute
lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous
leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also exist with a similar
etiology in other mammals, and can be treated by administering the pharmaceutical
compositions of the present invention.

The total amount of the active ingredient (compound of Formula I) to be administered
via the oral route using the pharmaceutical composition of the present invention will
generally range from about 0.01 mg/kg to about 50 mg/kg body weight per day.
Based upon standard laboratory techniques known to evaluate compounds useful for
the treatment of hyper-proliferative disorders, by standard toxicity tests and by
standard pharmacological assays for the determination of treatment of the conditions
identified above in mammals, and by comparison of these results with the results of
known medicaments that are used to treat these conditions, the effective dosage of the
pharmaceutical compositions of this invention can readily be determined by those
skilled in the art. The amount of the administered active ingredient can vary widely
according to such considerations as the particular compound and dosage unit
employed, the mode and time of administration, the period of treatment, the age, sex,
and general condition of the patient treated, the nature and extent of the condition
treated, the rate of drug metabolism and excretion, the potential drug combinations
and drug-drug interactions, and the like.

The pharmaceutical compositions of this invention can be administered as the sole
agent or in combination with one or more other therapies where the combination
causes no unacceptable adverse effects. For example, they can be combined with
cytotoxic agents, signal transduction inhibitors, or with other anti-cancer agents or
therapies, as well as with admixtures and combinations thereof.

In one embodiment, the pharmaceutical compositions of the present invention can be
combined with cytotoxic anti-cancer agents. Examples of such agents can be found in

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the 11 Edition of the Merck Index (1996). These agents include, by no way of
limitation, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin,
colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin,
doxorubicin (adriamycine), epirubicin, etoposide, 5 -fluoro uracil,
hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine,
mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C,
mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin,
tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other cytotoxic drugs suitable for use with the pharmaceutical compositions of the
invention include, but are not limited to, those compounds acknowledged to be used
in the treatment of neoplastic diseases in Goodman and Oilman* s The
Pharmacological Basis of Therapeutics (Ninth Edition, 1996, McGraw-Hill). These
agents include, by no way of limitation, aminoglutethimide, L-asparaginase,
azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2\ T-
difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-
fluorodeoxy uridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate,
fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon,
medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel,
pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine,
teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and
vinorelbine.

Other cytotoxic anti-cancer agents suitable for use in combination with the
compositions of the invention also include newly discovered cytotoxic principles such
as oxaliplatin, gemcitabine, capecitabine, epothilone and its natural or synthetic
derivatives, temozolomide (Quinn et al., J. Clin. Oncology 2003, 27(4), 646-651),
tositumomab (Bexxar), trabedectin (Vidal et al., Proceedings of the American Society
for Clinical Oncology 2004, 23, abstract 3181), and the inhibitors of the kinesin
spindle protein Eg5 (Wood et al., Curr. Opin, Pharmacol. 2001, 7, 370-377).

In another embodiment, the pharmaceutical compositions of the present invention can
be combined with other signal transduction inhibitors. Of particular interest are signal

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transduction inhibitors which target the EGFR family, such as EGFR, HER-2, and
HER-4 (Raymond et aL, Drugs 2000, 60 (Suppl.l), 15-23; Harari et al., Oncogene

2000, 19 (53), 6102-6114), and their respective ligands. Examples of such agents
include, by no way of limitation, antibody therapies such as Herceptin (trastuzumab),
Erbitux (cetuximab), and pertuzumab. Examples of such therapies also include, by no
way of limitation, small-molecule kinase inhibitors such as ZD-1839 / Iressa (Baselga
et aL, Drugs 2000, 60 (Suppl. 1), 33-40), OSI-774 / Tarceva (Pollack et aL J. Pharm.
Exp, Ther. 1999, 20/(2), 739-748), CI- 1033 (Bridges, Curr. Med Chem. 1999, 6,
825-843), GW-2016 (Lackey et aL, 92 nd AACR Meeting, New Orleans, March 24-28,

2001, abstract 4582), CP-724,714 (Jani et aL, Proceedings of the American Society
for Clinical Oncology 2004, 23, abstract 3122), HKI-272 (Rabindran et aL, Cancer
Res. 2004, 64, 3958-3965), and EKB-569 (Greenberger et aL, 11 th NC1-EORTC-
AACR Symposium on New Drugs in Cancer Therapy, Amsterdam, November 7-10,
2000, abstract 388).

In another embodiment, the pharmaceutical compositions of the present invention can
be combined with other signal transduction inhibitors targeting receptor kinases of the
split-kinase domain families (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fms, and the
like), and their respective ligands. These agents include, by no way of limitation,
antibodies such as Avastin (bevacizumab). These agents also include, by no way of
limitation, small-molecule inhibitors such as STI-571 / Gleevec (Zvelebil, Curr
Opin. Oncol, Endocr. Metab. Invest. Drugs 2000, 2(1), .74-82), PTK-787 (Wood et
aL, Cancer Res. 2000, 50(8), 2178-2189), SU-11248 (Demetri et aL, Proceedings of
the American Society for Clinical Oncology 2004, 25, abstract 3001), ZD-6474
(Hennequin et aL, 92 nd AACR Meeting, New Orleans, March 24-28, 2001, abstract
3152), AG-13736 (Herbst et aL, Clin. Cancer Res. 2003, 9, 16 (suppl 1), abstract
C253), KRN-951 (Taguchi et aL, 95 th AACR Meeting, Orlando, FL, 2004, abstract
2575), CP-547,632 (Beebe et aL, Cancer Res. 2003, 63, 7301-7309), CP-673,451
(Roberts et aL, Proceedings of the American Association of Cancer Research 2004,
45, abstract 3989), CHIR-258 (Lee et aL, Proceedings of the American Association of
Cancer Research 2004, 45, abstract 2130), MLN-518 (Shen et aL, Blood 2003, 102,
11, abstract 476), and AZD-2171 (Hennequin et aL, Proceedings of the American
Association of Cancer Research 2004, 45, abstract 4539).

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In another embodiment, the pharmaceutical compositions of the present invention can
be combined with inhibitors of the Raf/MEK/ERK transduction pathway (Avruch et
al., Recent Prog. Horm. Res, 2001, 56, 127-155), or the PKB (akt) pathway (Lawlor
et al., J. Cell Sci. 2001, J 14, 2903-2910). These include, by no way of limitation, PD-
325901 (Sebolt-Leopold et al., Proceedings of the American Association of Cancer
Research 2004, 45, abstract 4003), and ARRY-142886 (Wallace et al., Proceedings
of the American Association of Cancer Research 2004, 45, abstract 3891).

In another embodiment, the pharmaceutical compositions of the present invention can
be combined with inhibitors of histone deacetylase. Examples of such agents include,
by no way of limitation, suberoylanilide hydroxamic acid (SAHA), LAQ-824
(Ottmann et al., Proceedings of the American Society for Clinical Oncology 2004, 23,
abstract 3024), LBH-589 (Beck et aL, Proceedings of the American Society for
Clinical Oncology 2004, 23, abstract 3025), MS-275 (Ryan et aL, Proceedings of the
American Association of Cancer Research 2004, 45, abstract 2452), and FR-901228
(Piekarz et al., Proceedings of the American Society for Clinical Oncology 2004, 23,
abstract 3028).

In another embodiment, the pharmaceutical compositions of the present invention can
be combined with other anti-cancer agents such as proteasome inhibitors, and m-TOR
inhibitors. These include, by no way of limitation, bortezomib (Mackay et al.,
Proceedings of the American Society for Clinical Oncology 2004, 23, Abstract 3109),
and CCI-779 (Wu et al., Proceedings of the American Association of Cancer
Research 2004, 45, abstract 3849).

Generally, the use of cytotoxic and/or cytostatic anti-cancer agents in combination
with the pharmaceutical compositions of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or even eliminate
the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administered

agents,

(3) provide for a chemotherapeutic treatment protocol that is well tolerated in
the patient with fewer deleterious pharmacological complications than observed with
single agent chemotherapies and certain other combined therapies,

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(4) provide for treating a broader spectrum of different cancer types in
mammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients compared to
standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those of the agents
used alone, compared to known instances where other cancer agent combinations
produce antagonistic effects.

It is believed that one skilled in the art, using the preceding information and
information available in the art, can utilize the present invention to its fullest extent.

It should be apparent to one of ordinary skill in the art that changes and modifications
can be made to this invention without departing from the spirit or scope of the
invention as it is set forth herein.

All publications, applications and patents cited above and below are incorporated
herein by reference.

Example 1 refers to a preparation of the compound used in this invention.
Representative solid dispersion formulations of the compound of this invention are
described in Examples 2, 3, and 4.

Examples

Example 1: Preparation of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-
phenoxy}-pyridine-2-carboxylic acid methyl amide

A method of preparing BAY 43-9006 (4{4-[3-(4-chloro-3-trifluoromethylphenyl>
ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide) is described in Bankston
et al. "A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the
Treatment of Cancer" Org. Proc. Res. Dev. 2002, 6(6), 777-781.

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Example 2: Preparation of 1:1, 1:2, 1:3, 1:4, and 1:5 solid dispersion of the
compound of Example 1 with polyvinylpyrrolidone.

In an uncapped vial, one part of the compound of Example 1 as a free base was mixed
with one, two, three, four, or five parts polyvinylpyrrolidone (PVP-25 / Kollidon 25)
respectively. The mixture was dissolved in a sufficient amount of a 5 to 1 mixture of
acetone and ethanol, until all powders were in solution. The uncapped vial was placed
into a vacuum oven set at 40°C, and let dry for at least 24 hours.

The in vitro dissolution properties of the pharmaceutical compositions of Example 2
are compared with those of the free base of Example 1 as depicted in the dissolution
profile below.

Based on this data, it can be assumed that the oral administration of the compound of
the present invention, as a solid dispersion, will result in an improved absorption and
bioavailability in humans, compared with a conventional formulation.

Dissolution Profile

Time [min]

In vitro dissolution profiles of solid dispersions of the compound of the present
invention in various amounts of polyvinylpyrrolidone (ratios ranging from 1:1 to 1:5).

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Example 3: Preparation of a 1:3 solid dispersion of the compound of Example 1
with hydroxypropyl cellulose.

In a heat-resistant vessel, one part of the compound of Example 1 as a free base was
thoroughly mixed with three parts of hydroxypropyl cellulose (HPC-L), melted
together at a temperature of > 200°C on a heating plate, then cooled back to room
temperature.

Example 4: Preparation of a 1:5 solid dispersion of the compound of Example 1
with starch and polyethylene glycol.

In a heat-resistant vessel, one part of the compound of Example 1 as a free base was
thoroughly mixed with 4 parts of starch and one part of polyethylene glycol (PEG
6000), melted together at a temperature of > 200 °C on a heating plate, and then cooled
to room temperature.

It is believed that this new type of pharmaceutical composition, comprising a solid
dispersion of the compound of Formula I, will result in improved bioavailability,
improved inter-patient variability, and overall superior efficacy for the treatment of
hyper-proliferative diseases, including cancer.

Based on these findings it can be assumed that this new type of pharmaceutical
composition, comprising a solid dispersion of the compound of Formula I, will result
in improved absorption and exposure, reduced inter-patient variability, and overall
superior efficacy for the treatment of hyper-proliferative disorders, including cancer.

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What is Claimed is ;

1 . A composition containing 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-
phenoxy}-pyridine-2-carboxylic acid methyl amide and/or salts, hydrates, solvates
thereof in the form of a solid dispersion.

2. A composition comprising a solid dispersion comprising at least the compound of
Formula I and a pharmaceutical^ acceptable matrix.

H H

3. A composition according to claim 2, wherein the matrix comprises polymeric
excipients or non-polymeric excipients capable of dissolving or dispersing the
compound of Formula I.

4. A composition according to claim 2, wherein the matrix comprises a combination
of polymeric excipients and non-polymeric excipients capable of dissolving or
dispersing the compound of Formula I.

5. A composition according to claim 2, wherein the matrix comprises a water soluble
polymer,

6. A compositions according to claim 5, wherein the matrix comprises at least one
polymer from the group consisting of polyvinylpyrrolidone, copovidone,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycole or
polyethylene oxide.

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7. A composition according to claim 6, wherein the matrix comprises
polyvinylpyrrolidone .

8. A composition according to claim 7, wherein the weight ratio of the compound of
Formula I calculated as solvent-free base to polyvinylpyrrolidone is between 1:0.5
and 1:20.

9. A composition according to claim 6, wherein the matrix comprises hydroxypropyl
cellulose.

10. A composition according to claim 9, wherein the weight ratio of the compound of
Formula I calculated as solvent-free base to hydroxypropyl cellulose is between
1:0.5 and 1:20.

1 1 . A composition according to any of the proceeding claims, wherein the solid
dispersion comprises croscarmellose sodium, sodium starch glycolate, crospovi-
done, low substituted hydroxypropyl cellulose, starch, microcrystalline cellulose
or a combination thereof.

12. A composition according to claim 8, wherein the solid dispersion comprises
polyvinylpyrrolidone and croscarmellose sodium.

13. A composition according to claim 8, wherein the solid dispersion comprises
polyvinylpyrrolidone and sodium starch glycolate.

14. A composition according to claim 8, wherein the solid dispersion comprises
polyvinylpyrrolidone, croscarmellose sodium and microcrystalline cellulose.

15. A composition according to claim 10, wherein the solid dispersion comprises
hydroxypropyl cellulose and croscarmellose sodium.

16. A composition according to claim 10, wherein the solid dispersion comprises
hydroxypropyl cellulose and at least one excipient which is a sugar, sugar alcohol,
cyclodextrin.

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17. A composition according to any of the proceeding claims, wherein the solid
dispersion is substantially homogeneous.

18. A composition according to any of the proceeding claims, which contains the
compound of Formula I in substantially amorphous form.

19. A composition as claimed in any one of the proceeding claims, which is a
pharmaceutical composition for oral application.

20. A composition as claimed in any one of the proceeding claims, which is a
pharmaceutical composition in the form of a tablet.

21. A composition as claimed in any one of the proceeding claims, which is a
pharmaceutical composition in the form of a capsule.

22. A composition as claimed in any one of the proceeding claims, which is a
pharmaceutical composition in the form of a powder, granulate or sachet.

23. A process for the preparation of a solid dispersion of the compound of Formula I

which comprises simultaneously exposing the compound of Formula I and at
least one matrix to hot melt extrusion, hot melt coating, prilling, congealing,
solvent evaporation techniques or a combination thereof.

24. A process according to claim 23, wherein the solid dispersion is prepared by
exposing the compound of Formula I and at least one matrix agent to hot melt
extrusion.

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25. A process according to claim 23, wherein the solid dispersion is prepared by
exposing the compound of Formula I and at least one matrix agent to solvent
evaporation techniques.

26. A process as claimed in claim 23 to 25 wherein the solid dispersion is further
treated with at least one additional processing step, which is milling, sieving,
roller compaction, grinding, screening, mixing or a combination thereof.

27. A process as claimed in claim 23 to 26 comprising the additional step of
compounding the solid dispersion with one or more pharmaceutical acceptable
excipients to form a mixture and shaping this mixture into tablets, filled capsules
or sachets.

28. A pharmaceutical composition, produced by a process of claims 23 to 27,

29. A method for treatment of hyper-proliferative disorders comprising administering
a pharmaceutical composition according to any of the claims 1 to 22 and 28 to a
mammal, including a human, either as sole agent or in combination with other
therapies.

30. A method for treatment of cancer comprising administering a pharmaceutical
composition according to any of the claims 1 to 22 and 28 to a mammal, including
a human, either as sole agent or in combination with other therapies.

3 1 . A method for treatment of cancer comprising administering a pharmaceutical
composition according to any of the claims 1 to 22 and 28 to a mammal, including
a human, either as sole agent or in combination with radio therapy.

32. A method for treatment of cancer comprising administering a pharmaceutical
composition according to any of the claims 1 to 22 and 28 to a human patient, in
combination with a cytotoxic therapy.

33. A method for treatment of cancer comprising administering a pharmaceutical
composition according to any of the claims 1 to 22 and 28 to a human patient, in
combination with another anti-cancer therapy targeting either VEGFR, PDGFR,

WO 2006/026501 PCT/US2005/030542

src, abl flt-3, EGFR, HER-2, aurora, raf, MEK, ERK, PI-3 kinase, AKT, mTOR,
or HDAC.

INTERNATIONAL SEARCH REPORT

I tional Application No

. W./US2005/030542

A. CLASSIFICATION OF SUBJECT MATTER

A61K9/14

According lo International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)

A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practical, search terms used)

EPO-Internal , WPI Data, PAJ, CHEM ABS Data

C. DOCUMENTS CONSIDERED TO BE RELEVANT

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